Hyenas: the “how” of female masculinization (Part 3)

In part 3 we will discuss normal mammalian testosterone metabolism using a simple input/output model. We will first look at its basic biochemistry & its influence on external genital development in the fetus. Finally in part 4, using this basic input output model we will summarize current theories on how excessive testosterone activity induces masculinization in the female hyena.

It is easiest if we briefly discuss human sexual development, as so much is known about it. Some very successful female athletes, with masculine features have attracted a lot of attention recently. Their prowess is not always induced knowingly ingesting male hormones to increase their muscular strength. Some female athletes may have been born with abnormalities in their sexual differentiation &/or testosterone metabolism. For example they may have higher testosterone levels than those normally found in women.

The rudimentary genitals of male & female embryos initially look the same until the sex determining genes begin to induce differences. Have a look at the excellent chapters on embryology of the genitalia from the Universities of Fribourg, Lausanne and Bern in Switzerland. Until recently it was believed that the female form was the default template for the mammalian fetuses of both sexes. The female with XX sex chromosome pair develops internal (ovaries, ovarian ducts, &uterus) & external (vagina, clitoris, & labia) female genitalia. But even an XO female, who won’t develop ovaries will still develop the ‘default” external genitalia i.e. vagina, clitoris, & labia. However the male, with the XY chromosome sex chromosomes has a testis determining gene on the Y chromosome. As it differentiates the testis will produce two essential developmental hormones testosterone & Anti-Mullerian Hormone. Testosterone will alter the default pattern of the external genitalia with the clitoris forming a penis and the labia fusing to form the scrotum. Anti-Mullerian hormone induces regression of the internal female genitalia, which are normally derived from parts of the embryonic kidney called the Mullerian duct. This paradigm of sexual development is however now being challenged;  there are also genes that determine  the female phenotype.

Introduction the Input & Output of Testosterone :-

Testosterone is a member of the steroid family of organic compounds. The parent molecule for the whole family is cholesterol. The basic input & output of the cholesterol molecule is shown in figure 1.

cholesterol metabolism

Cholesterol is the parent molecule of the steroid hormones such as the feminizing estrogens e.g. estradiol & masculinizing androgens e.g. testosterone. (click to enlarge)

This well-known molecule consists of 27 carbon (C) atoms linked together to form 4 rings & a tail ( see top right of figure 1).  Each of the carbon atoms has free arms & to these are attached a total of 45 hydrogen atoms and one OH group.  Various enzymes can cleave the tail  at various positions to produce smaller molecules of 21, 19, or 18 C atoms. These molecules can then be altered by attaching other molecules to the rings or the tail. This produces the many members of the steroid family: C21 glucorticoids e.g. cortisol, C19 androgens e.g. testosterone & C18 estrogens e.g. estriol.

Testosterone Metabolism

A simple model on how testosterone levels are regulated & the hormone transported via the plasma to the cell  & then cytoplasm to the target genes in the nucleus of cells. (Click to enlarge)

The testosterone level will depend on balance between the amount produced and broken down i.e. its input & output (Figure 2).

Testosterone is produced in the not only in the testis (largest amount), but also in other organs i.e. ovary, adrenal gland, skin, & placenta. It is formed from cholesterol following a complex chain of enzymatic reactions. Its output can follow a number of paths. It can be converted to an even more powerful masculinizing hormone called dihydrotestosterone or converted by the aromatase enzyme into estradiol, a member of the feminizing estrogen hormone family. Testosterone, like its parent molecule cholesterol is lipid soluble i.e. not water soluble, & must be transported to the tissues bound to a specific plasma protein, the sex hormone binding globulin (SHBG). The testosterone however easily crosses the lipid cell membranes & binds with a specific protein carrier present in the cell cytoplasm. It is then carried into the nucleus where it binds with specific genes (see “lock & key model) & induces transcription of masculinizing proteins. The plasma level of testosterone is regulated by the liver. There it is broken down (catabolism) & these end products are joined (conjugated) to other compounds e.g. sulfates which are water soluble and thus easily excreted via the urine.

So in summary the metabolic pathway of testosterone is production (input) in various organs (testis, ovary, adrenals, & skin), transport in the blood plasma bound to a protein (SHBG) to target cells, release at cell wall and diffusion across into the cell cytoplasm, binding with a specific receptor which carries it into the nucleus where it binds & activates specific genes. Finally it is excreted (output) via the liver & kidneys

Tulane University has produced on their e.hormone site simple & very useful animations to explain the above

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